Nu-substituted azepines and dihydroazepines



United States PatentC N-SUBS TITUTED AZEPINES .AND DIHYDRO- AZEPINES Walter Schindler, Riehen, nearBasel, Franz Hafliger,

Basel, and Henri Dietrich, Birsfelden, Basel Land, Switzerland, assignors to Geigy Chemical Corporation, Ardsley, N.Y., .a corporation of Delaware No Drawing. Filed Mar; 17, 1959,Ser. No. 799,842 Claims priority; application SwitzerlandMar.-20, 1958 5' Claims: (Cl. 260-239) The present invention relates to new N-heterocyclic' compounds having valuablepharmacoogical properties; as we'll asto processes for the production thereof.

N-substituted azepines and dihydroazepines of the general formula O-I| T-CHz-CHN\ R: I wherein X represents the ethylene or vinylene group (CH -CH 0r It has'now been found that these. compounds have valuable pharmacological properties, in. particular, local anaesthetic activity.

The tertiary bases defined above can be produced by reacting. reactive functional.derivativesof 1.0;ll-dihydro-' -dibenz0[b.f] azepine-S-carboxylic acids or 5-dioenzo- [b.f]azepine-S-carboxylic acids, termed in the following as iminodibenzyl or iminostilbene-S-carboxylic acidsrespcctively, which correspond to the general formula;

(10011 11 wherein X, Y and'Z 'have the m'eanings given above, in particular reacting the chlorides, bromides or low molecular alkyl esters of these N-carboxylic acids which do not exist in the free form, with N,N-disubstituted or N,N,N-trisubstituted ethylene diamines of the general formula /R1,. H-III-C Hr-C Hz-N R3 35- III wherein R R R and n-have 'the-meanings'given above. Thereactions'can be performed, forexample, at temperatures 'of'about"100-200 inthe presence or absence'of inert solvents such as toluene or xylene. An' excess' of theethylene diaminederivative'ofFormula III used for the reaction can lie-used to blndthehydrogen chloride 2,%5,638 Patented Dec. 20,1950

liberated by the reactionwith acid halides and also as diluent.

The new compounds of the general Formula I can also be produced by reacting N-halogen alkyl amides of acids of the general Formula Ilwhich. correspond to the. general formula 0-1II-C Hi- 0 Err-Hal Ra IV and wherein X, Y, Z and R have the meanings given above, and Hal represents. chlorine or bromine, with secondaryamines of the general formula whereinR andR have' the meanings given above. In this case, an excess of the secondary amine used for the reaction is advantageously used as acid binding agent. The reaction is performed in the presence or absence of an inert organic solvent or diluent at a raised tempera= ture, if'necessary in a closedvessel. The reaction of .the.N=,N-ethyleneamide-of an acid of the general FormulaIl, corresponding to the general formula wherein X, Y and Z havethe meanings given above, with a secondary amine of the general Formula V can. serve asa particular method of performing, this process for the production of compounds of the. general Formula I in. which R is hydrogen.

Examples .of reactive functional derivatives of acids of the general Formula II are iminodibenzyl-S-carbonyli chloride, 3-ch1oroor 3-bromo-iminodibenzyl-5rcarbonyl. chloride, 3.7-dichloroor 3.7-dibromo-iminodbenzyl-S- carbonyl chloride, iminostilbene-S-carbonyl chloride 3.-

chloroor 3 bromo-iminostilbene-S-carbonyl chloride.

and, 3.7-dichloroor 3.7-dibromo-iminostilbeneeficarbone yl chloride. These are obtained by reacting pnosgene. with the corresponding iminodibenzyls or iminostilbenes. The latter, in their. turn, are obtained from theknown iminodibenzyl (10,1l-dihydro-S-dibenzoibil azepine) or the C-substitution products thereof by N-acylatiomtbromirtation. in the l0position with bromosuccinimide and then eithersubsequent or simultaneous splitting off of. hydrogen bromide and hydrolysis, for example, by means. ofalkalilyes.

Ethylene diamines of the general Formula III suitable for reaction with the functional derivatives of. acidslof the general Formula II given above, are, for exampler N,N-dimethyl-, N,N-diethyl-, N,N-di.-n-propyl-, N,N-di=. n-butyl-, N,N,N-trimethyl-, N,N,N'-triethyl;,, N,N-dimethylTN'-ethyl-, N,N-dimethy l-.N-n-propyl, N,N-dimethy1-N-isopropyl-, N,N dimethyl-N'm-butyh, diethyLN methyI- and N,N-die thyl-N-n-butylethylene. diamine, as well as .N-(fl-pyrrolidino-ethyll ,N-(Bpipei idino ethyl), and" N-(p morpholino-ethyllramine, -metliylarnine, -ethylamineand -n-'butylamine.

The N-nalogen alkylamides necessary tor the second production process are obtained, for example, by reacting iminodibenzylor iminostilbene-N-carboxylic acids withhalogen, alkylamines analogously to the'first production process. Examples of starting materials of the general Formulas IV and VI are the N-(fi-chlorethyD- amides, N-(fl-bromo-ethyD-amides and N,N-ethylene amides of iminodibenzyl-S-carboXylic acid, 3.7-dichloroi'minodibenzyl-S-carboxylic acid and of iminostilbene-S- carboxylic acid.

The compounds produced according to the present invention having a tertiary basic amino group form salts, some of which are water soluble, with therapeutically compatible inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methane'sulphonic acid, ethane disulphonic acid, acetic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, benzoic acid and phthalic acid. By reacting the tertiary basic compounds with reactive esters, in particular halides and sulphates of-aliphatic or araliphatic alcohols, with, for example, methyl iodide, d-imethyl sulphate, ethyl bromide, ethyl iodide, diethyl sulphate, n-propyl bromide, n-butyl bromide, allyl bromide, allyl iodide, benzyl chloride, benzyl bromide, p-chlorobenzyl chloride or phenoxyethyl bromide, quaternary ammonium salts are obtained which also have valuable pharmacological properties, for example, spasmolytic activity.

The compounds according to the present invention, when used as local anaesthetics may be administered in the form of a 15% aqueous solution of their salts.

benzyl-S-carboxylic acid-N-diethylaminoethyl amide may also be termed 5-(Ndiethylaminoethyl-carbamyl)-imino dibenzyl.

Iminodlbenzyl 5 carboxylic acid-N-n-butyl-N-(p-pyrrolidinoethyl)-amide or, using the alternative nomenclature, S-[N-n-butyl N (fl-pyrrolidinoethyl)-carbamyl]- iminodibenzyl (M.P. of hydrochloride: 220-222") is 'obtained in an analogous manner.

Example 2 25.7 parts of iminodibenzyl-S-carboxylic acid chloride are dissolved in 100 parts by volume of abs. benzene and a solution of 14.0 parts of bromethylamine in 50 parts I lye whereupon the base precipitates and is recrystallised from ether. The iminodibenzyl-S-carboxylic acid-N-diethylarni-noethylamide so obtained melts at 97.

The following compounds, for example, are obtained in an analogous manner by the processes described in the above examples from 3-chloroor 3-bromo-iminodibenzyl- The most important compounds are those according to Formula I wherein Y and Z-mean hydrogen or 2 means chlorine in 3-position and R and R mean lower alkyl radicals, or R and R jointly withthe N atom to which they are bound, mean the pyrrolidino radical.

The following examples further illustrate the production of the new compounds. 'Parts are given as parts by weight and their relationship to parts by volume is as that of grammes to cubic centimetres. The temperatures are in degrees centigrade.

Example I 18.5 parts of iminostilbene-S-carboxylic acid chloride and 50 parts by volume of N,N-dimethyl-N'-butyl-ethylene diamine are heated for 2 hours in an oil bath at 160. The reaction mixture is then cooled, poured into water and thoroughly ethered out. The basic portions are removed from the ethereal solution by shaking out four dibenzyl-S-carbonyl chloride and 50 parts by volume of N,N,N'-trimethylethylene diamine, the hydrochloride of iminodibenzyl 5 carboxylic acid-N-methyl-N-dimethylaminoethyl amide [5-(N-methyl-N-dimethylaminoethylcarbamyl)-iminodibenzyl] is obtained, M.P. 236-238. If .l 8.6.parts of iminodibenzyl-S- carbonyl chloride or 22 parts of 3.7 dichloro iminodibenzyl-5-carbonyl chloride are'reacted according to the above example with 50 or 60 parts respectively of N.N-diethyl-ethylene diamine, on concentrating the ether extracts of the acetic acid solutions which have been made alkaline, iminodibenzyl-S-car- 'boxylic acid-N-diethylaminoethyl amide (M.P. 97 after recrystallisation from 'ether) or 3.7:dibhloro-irriinodi benzyl-5--carboxylic acid-N diethylaminoethyl amide-"respectively precipitate in crystalline for yTh i minodi- S-carboxylic acid chloride or 3-chloroor 3-bromo= iminostilbene-S-carboxylic acid chloride:

3-chloro-iminodibenzyl-5-carboxylic acid-N-methyl-N-di methylaminoethylamide,

h 3tchloro-iminodibenzyl-5-carboxylic acid N ethyl-N-(pmorpholinoethyl)-amide, 3,-chloro-iminodibenzyl-5-carboxylic acid-N-diethylaminoethyl amide, M.P. 9'7-98, M.P. of hydrochloride 127-- 1285, I 3-chloro-iminostilbene-S-carboxylic acid-N-diethylarnino ethyl amide, M.P. of hydrochloride 155, 3-chloro-iminostilbeneS-carboxylic acid-N-(fl-pyrrolidinoethyl)-N-n-butyl amide,

: 3-chloro-iminodibenzyl 5 carboxylic acid-N-(p-pyrrolidinoethyl)-N-n-butyl amide, 3-chloro-iminodibenzyl 5 carboxylic acid-N-(B-pyrrolidino-ethyU-N-n-butyl amide, 3-bromo-iminostilbene-S-carboxylic acid-N-diethylamino ethyl amide, 3-bromo-iminostilbene-S-carboxylic acid-N-diethylaminoethyl-N-methyl amide t What we claim is;

1.. An N-heterocyclic compound of the formula Y I l,.z

I wherein X represents a member selected from the group consisting of the ethylene and vinylene group, each of Y and 2 represents a member selected from the group consisting of hydrogen, chlorine and bromine, and each of R, and R taken separately represents a lower alkyl radical I ,and. R and R, jointly with the N-atom to which they. .are bound represent a member selected from the group consisting of the pyrrolidino, piperidino and morpholino radical, and I R represents a member'selected from the group consist ing of hydrogen and a lower alkyl radical. 

1. AN N-HETEROCYCLIC COMPOUND OF THE FORMULA 